1-erythro-2-Amino-1-phenyl-1-propanol, 1, is a naturally occurring alkaloid found in the Chinese herb ‘Ma Huang’. It is isolated from the herb along with 1-ephedrine and other alkaloids.

Apart from the natural source, this material has been produced synthetically also. The synthetic methods can be broadly classified into following categories:
1. Resolution of dl-phenylpropanolamine, which in turn is prepared by:
i) catalytic hydrogenation of alpha-isonitrosopropiophenone (scheme 1)
ii) alpha halogenation of propiophenone, amination followed by catalytic hydrogenation. (scheme 2, X=halogen)
iii) Reduction of 1-phenyl-2-nitro-1-propanol (scheme 3)
2. Catalytic hydrogenation of 1-1-phenyl-1-hydroxy-2-propanone in the presence of ammonia or aralkylamines. (Scheme 4, R═H, aralkyl)
3. Reduction of derivatives like oximes, hydrazones or imines of 1-1-phenyl-1-hydroxy-2-propanone by catalytic hydrogenation, which may be effected by chiral or achiral catalysts or by dissolving metals or metal amalgams. (Scheme 5, R═OH, NH2, aralkyl)
4. Resolution of 2-amino-1-phenyl-1-propanone followed by catalytic hydrogenation of optical antipode of 2-amino-1-phenyl-1-propanone (Scheme 6)
5. Stereospecific synthesis using chiral precursors with known stereochemistry or chiral auxiliaries.
The resolution of dl-phenylpropanolamine has been tried by employing many resolving agents
S. Kanao, J. Pharm. Soc. Japan 48, 947-958 (1928); E. Flassig, Oesterreich Chemiker Zeitung 57, 308 (1956); and J. Org. Chem. 25, 1929-1937 (1960) disclose use of L-tartaric acid as a resolving agent.
C. Jarowsky; W. H. Hartung, J. Org. Chem. 8, 654 (1943) disclose use of L-mandelic acid as a resolving agent.
H. Takamatsu, J. Pharm. Soc. Japan 76, 1230-1233 (1956) disclose use of camphorsulphonic acid as a resolving agent.
Several patent documents also disclose methods for resolving dl-phenylpropanolamine using various resolving agents. Some of these patents are incorporated below for reference.
German Patents 2,258,410 (1973); 2,304,055 (1974) and 2,258,410 (1974) and British Patent 1,385,490 (1975) disclose resolution of dl-phenylpropanolamine employing thiazolidinecarboxylic acids.
German Patent 2,258,507 (1976) discloses resolution of dl-phenylpropanolamine using pantoic acid.
German patents 2,854,069 (1979) and 2,854,070 (1979) demonstrate use of maleamides of d- and 1-norpseudoephedrine in resolving dl-phenylpropanolamine.
Japanese Patent 4530 (1955) discloses resolution of dl-phenylpropanolamine using (2R,3R)-2,3-dimethoxy succinic acid.
However, none of these resolving agents used in prior art give good yields of optically pure antipodes of phenylpropanolamine. Besides, the cost and difficulty in recovery of these resolving agents is of great concern.
In addition, the starting material dl-phenylpropanolamine itself has been prepared by a number of methods
U.S. Pat. No. 3,028,429 (1962); W. H. Hartung; J. C. Munch, J. Am. Chem. Soc. 51, 2262-2266 (1929); U.S. Pat. No. 2,784,228 (1957); W. H. Hartung, Y. Chang, J. Am. Chem. Soc. 74, 5927-5929 (1952); H. Adkins, H. R. Billica, J. Am. Chem. Soc. 70, 695-698 (1948); M. C. Rebstock; G. W. Moersch; A. C. Moore and J. M. Vandenbelt, J. Am. Chem. Soc. 73, 3666-3670 (1951) and T. Matsumoto; K. Hata, J. Am. Chem. Soc. 79, 5506 (1957) describe in details the preparation of dl-phenylpropanolamine by catalytic hydrogenation of alpha-isonitrosopropiophenone with metal catalysts such as Ni, Pd, Pt etc.
J. R. Merchant, R. K. Pandya, J. N. Ray, Science and Culture, Calcutta 23, 313-314 (1957) describe the preparation of dl-phenylpropanolamine by reduction of alpha-isonitrosopropiophenone with aluminum amalgam.
D. H. Hey, J. Chem. Soc. 1232 (1930) demonstrate the preparation of dl-phenylpropanolamine by reduction of alpha-isonitrosopropiophenone with sodium/ethanol
V. Evdokimoff, Gazz. Chim. Ital. 81, 725 (1951) describe the preparation of dl-phenylpropanolamine by reduction of alpha-isonitrosopropiophenone with nickel-aluminium (1:1) alloy.
Other methods of preparation of dl-phenylpropanolamine as described in German Patent 468,306 (1925); H. K. Mueller, Annallen 598, 70-84 (1956) and P. Besse, H. Veschambre, J. Org. Chem. 59, 8288-8291 (1994) include reduction of 2-aminopropiophenone, which in turn is obtained by a) halogenation of propiophenone and reaction with ammonia, b) reaction of halogenated propiophenone with sodium azide followed by reduction of alpha-azidopropiophenone.
Racemic phenylpropanolamine is also obtained by reduction of 1-phenyl-2-nitro-1-propanol as discussed in literatures like N. Wilhelm; Nagai; S. Kanao, Annallen 470, 157-182 (1929); S. Kanao, J. Pharm. Soc. Japan 48, 947-958 (1928); Y. Shirozaki, J. Pharm. Soc. Japan 51, 720-722 (1931); F. W. Hoover, H. B. Hass, J. Org. Chem. 12, 506 (1947) as well as disclosed in patent documents U.S. Pat. No. 2,151,517 (1939) and British Patent 1,413,930 (1975).
These methods however have potential problems regarding poor efficiencies of conversion, contamination with diastereomeric impurities, which necessitate laborious purifications and catalyst cost.
Other methods as disclosed in German Patents 588,880 (1933); 587,586 (1933); 599,433 (1934); British Patents 365,535 (1930); 365,541 (1930); Indian Patent IN172,970 (1994) as well as exemplified in P. M. Subramanian; S. K. Chatterjee and M. C. Bhatia, J. Chem. Tech. Biotechnol. 39, 219-229 (1987) involving reductive amination of 1-1-phenyl-1-hydroxy-2-propanone are also riddled with problems.
The starting material, 1-1-phenyl-1-hydroxy-2-propanone, being an alpha-ketol, is very sensitive to extreme pH and temperature conditions. It is known to undergo very rapid racemization and isomerization to 2-hydroxy-1-phenyl-1-propanone in presence of traces of alkalies or acids (G. Richard, Compt. Rend. 214, 673 (1942)). Due to this the processes described in these references cause extensive racemization of 1-1-phenyl-1-hydroxy-2-propanone and subsequently lower the yields of 1-erythro-2-amino-1-phenyl-1-propanol.
In fact, low to medium yields of racemic phenylpropanolamine have been reported by this method in Indian Patent IN 172,970 (1994); P. M. Subramanian; S. K. Chatterjee and M. C. Bhatia, J. Chem. Tech. Biotechnol. 39, 219-229 (1987) in spite of starting with optically active 1-1-phenyl-1-hydroxy-2-propanone.
British Patent 365,535 (1930); German patent 1,014,553 (1957) and O. C. Kreutz; P. J. S. Moran and J. A. R. Rodrigues, Tetrahedron: Asymmetry 8, 2649-2653 (1997) have disclosed reduction of derivatives like oxime, hydrazone, N-benzylimine etc. of 1-1-phenyl-1-hydroxy-2-propanone. The oximes, oxime ethers and hydrazones of 1-1-phenyl-1-hydroxy-2-propanone have been reduced by catalytic hydrogenation and by aluminum amalgams.
European Patent EP 1,142,864 (2003) discloses reduction of N-benzylimine by catalytic hydrogenation.
Similarly, the approaches based on resolution of 2-amino-1-phenyl-1-propanone followed by reduction are not free from problems.
These approaches are disclosed in German patent 639,129 (1936); Japanese Patent JP 63091352 (1988) and literatures like H. Takamatsu, J. Pharm. Soc. Japan 76, 1219-1222 (1956) and B. D. Berrang, A. H. Lewin, F. I. Carroll, J. Org. Chem. 47, 2643-2647 (1982).
The starting material 2-amino-1-phenyl-1-propanone is stable only in salt form and unstable as a base and known to undergo self condensation to give undesired by-products which include 2,5-dimethyl-3,6-diphenyl-2,5-dihydropyrazine (M. Tiffeneau; J. Levy and E. Ditz, Bull Soc. Chim. 2, 1848 (1935) and S. Gabriel, Chem. Ber. 41, 1127-1156 (1908)). The resolution efficiency is poor and overall yield of the optically pure antipodes of erythro-2-amino-1-phenyl-1-propanol is also very low.
The catalytic hydrogenation of 2-amino-1-phenyl-1-propanone as described in F. Skita, F. Keil, E. Baesler, Chem. Ber. 66, 858 (1932), does not give exclusively erythro-product which is very essential for overall efficiency of the process.
One more method has been described in Jpn. Kokai Tokkyo Koho JP 0504948 [93,04948] (1993) in which alpha-isonitrosopropiophenone is asymmetrically hydrogenated in the presence of chiral substituted ferrocene catalysts. However this method also does not give a high diastereomeric and enantiomeric excess of one enantiomer of phenylpropanolamine over other and hence was not satisfactory.
Another approach is a stereospecific synthesis of 1-erythro-2-amino-1-phenyl-1-propanol from chiral precursors (T. F. Buckley; H. Rapoport, J. Am. Chem. Soc. 103, 6157-6163 (1981); K. Koga; H. Matsou and S. Yamada, Chem. Pharm. Bull. 14, 243-246 (1966); W. R. Jackson; H. A. Jacobs; G. S. Jayatilake; B. M. Matthews and K. C. Watson Aust. J. Chem. 43, 2045 (1990)) or by use of chiral auxiliaries. (W. Oppolzer; O. Tamura; G. Surendrababu and M. Signer, J. Am. Chem. Soc. 114, 5900 (1992))
In addition to the above, methods have been described by D. Enders; H. Lotter; N. Maigrot; J. P. Mazaleyrat and Z. Welvart, Nouv. J. Chem. 8, 747-750 (1984), and in Jpn. Kokai Tokkyo Koho JP 10 45688 (1998) in which alpha-isonitrosopropiophenone was either hydrogenated in the presence of hydrogenations having chiral ligands or reduced with borohydride complexes of 1,2-amino alcohol chiral auxiliaries.
A review of prior art methods shows that all the above stated methods suffer from at least one of the following drawbacks: cost and recyclability of hydrogenation catalyst, cost and recyclability of resolving agents, poor diastereo- and enantioselectivity in reductions, cost and availability of chiral precursors or chiral auxiliaries, cost and availability of chiral catalysts.
Thus there is a long felt consistent need to develop a process for the preparation of 1-erythro-2-amino-1-phenyl-1-propanol (1-Norephedrine) that bypasses the above limitations and is more efficient in terms of yield and resolution and at the same time is cost-effective.
These considerations have thus motivated the present inventors to address the existing need of a better and cost effective method for preparation of 1-erythro-2-amino-1-phenyl-1-propanol (1-Norephedrine).